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October 2016; 3 (5) ArticleOpen Access

Treatment of spontaneous EAE by laquinimod reduces Tfh, B cell aggregates, and disease progression

Michel Varrin-Doyer, Kara L. Pekarek, Collin M. Spencer, Claude C.A. Bernard, Raymond A. Sobel, Bruce A.C. Cree, Ulf Schulze-Topphoff, Scott S. Zamvil
First published September 21, 2016, DOI: https://doi.org/10.1212/NXI.0000000000000272
Michel Varrin-Doyer
From the Department of Neurology (M.V.-D., K.L.P., C.M.S., B.A.C.C., U.S.-T., S.S.Z.) and Program in Immunology (M.V.-D., K.L.P., C.M.S., U.S.-T., S.S.Z.), University of California, San Francisco; Multiple Sclerosis Research Group (C.C.A.B.), Australian Regenerative Medicine Institute, Monash University, Clayton, Australia; and Department of Pathology (R.A.S.), Stanford University, CA.
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Kara L. Pekarek
From the Department of Neurology (M.V.-D., K.L.P., C.M.S., B.A.C.C., U.S.-T., S.S.Z.) and Program in Immunology (M.V.-D., K.L.P., C.M.S., U.S.-T., S.S.Z.), University of California, San Francisco; Multiple Sclerosis Research Group (C.C.A.B.), Australian Regenerative Medicine Institute, Monash University, Clayton, Australia; and Department of Pathology (R.A.S.), Stanford University, CA.
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Collin M. Spencer
From the Department of Neurology (M.V.-D., K.L.P., C.M.S., B.A.C.C., U.S.-T., S.S.Z.) and Program in Immunology (M.V.-D., K.L.P., C.M.S., U.S.-T., S.S.Z.), University of California, San Francisco; Multiple Sclerosis Research Group (C.C.A.B.), Australian Regenerative Medicine Institute, Monash University, Clayton, Australia; and Department of Pathology (R.A.S.), Stanford University, CA.
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Claude C.A. Bernard
From the Department of Neurology (M.V.-D., K.L.P., C.M.S., B.A.C.C., U.S.-T., S.S.Z.) and Program in Immunology (M.V.-D., K.L.P., C.M.S., U.S.-T., S.S.Z.), University of California, San Francisco; Multiple Sclerosis Research Group (C.C.A.B.), Australian Regenerative Medicine Institute, Monash University, Clayton, Australia; and Department of Pathology (R.A.S.), Stanford University, CA.
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Raymond A. Sobel
From the Department of Neurology (M.V.-D., K.L.P., C.M.S., B.A.C.C., U.S.-T., S.S.Z.) and Program in Immunology (M.V.-D., K.L.P., C.M.S., U.S.-T., S.S.Z.), University of California, San Francisco; Multiple Sclerosis Research Group (C.C.A.B.), Australian Regenerative Medicine Institute, Monash University, Clayton, Australia; and Department of Pathology (R.A.S.), Stanford University, CA.
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Bruce A.C. Cree
From the Department of Neurology (M.V.-D., K.L.P., C.M.S., B.A.C.C., U.S.-T., S.S.Z.) and Program in Immunology (M.V.-D., K.L.P., C.M.S., U.S.-T., S.S.Z.), University of California, San Francisco; Multiple Sclerosis Research Group (C.C.A.B.), Australian Regenerative Medicine Institute, Monash University, Clayton, Australia; and Department of Pathology (R.A.S.), Stanford University, CA.
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Ulf Schulze-Topphoff
From the Department of Neurology (M.V.-D., K.L.P., C.M.S., B.A.C.C., U.S.-T., S.S.Z.) and Program in Immunology (M.V.-D., K.L.P., C.M.S., U.S.-T., S.S.Z.), University of California, San Francisco; Multiple Sclerosis Research Group (C.C.A.B.), Australian Regenerative Medicine Institute, Monash University, Clayton, Australia; and Department of Pathology (R.A.S.), Stanford University, CA.
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Scott S. Zamvil
From the Department of Neurology (M.V.-D., K.L.P., C.M.S., B.A.C.C., U.S.-T., S.S.Z.) and Program in Immunology (M.V.-D., K.L.P., C.M.S., U.S.-T., S.S.Z.), University of California, San Francisco; Multiple Sclerosis Research Group (C.C.A.B.), Australian Regenerative Medicine Institute, Monash University, Clayton, Australia; and Department of Pathology (R.A.S.), Stanford University, CA.
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Citation
Treatment of spontaneous EAE by laquinimod reduces Tfh, B cell aggregates, and disease progression
Michel Varrin-Doyer, Kara L. Pekarek, Collin M. Spencer, Claude C.A. Bernard, Raymond A. Sobel, Bruce A.C. Cree, Ulf Schulze-Topphoff, Scott S. Zamvil
Neurol Neuroimmunol Neuroinflamm Oct 2016, 3 (5) e272; DOI: 10.1212/NXI.0000000000000272

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Abstract

Objective: To evaluate the influence of oral laquinimod, a candidate multiple sclerosis (MS) treatment, on induction of T follicular helper cells, development of meningeal B cell aggregates, and clinical disease in a spontaneous B cell–dependent MS model.

Methods: Experimental autoimmune encephalomyelitis (EAE) was induced in C57BL/6 mice by immunization with recombinant myelin oligodendrocyte glycoprotein (rMOG) protein. Spontaneous EAE was evaluated in C57BL/6 MOG p35-55–specific T cell receptor transgenic (2D2) × MOG-specific immunoglobulin (Ig)H-chain knock-in (IgHMOG-ki [Th]) mice. Laquinimod was administered orally. T cell and B cell populations were examined by flow cytometry and immunohistochemistry.

Results: Oral laquinimod treatment (1) reduced CD11c+CD4+ dendritic cells, (2) inhibited expansion of PD-1+CXCR5+BCL6+ T follicular helper and interleukin (IL)-21–producing activated CD4+CD44+ T cells, (3) suppressed B cell CD40 expression, (4) diminished formation of Fas+GL7+ germinal center B cells, and (5) inhibited development of MOG-specific IgG. Laquinimod treatment not only prevented rMOG-induced EAE, but also inhibited development of spontaneous EAE and the formation of meningeal B cell aggregates. Disability progression was prevented when laquinimod treatment was initiated after mice developed paralysis. Treatment of spontaneous EAE with laquinimod was also associated with increases in CD4+CD25hiFoxp3+ and CD4+CD25+IL-10+ regulatory T cells.

Conclusions: Our observations that laquinimod modulates myelin antigen–specific B cell immune responses and suppresses both development of meningeal B cell aggregates and disability progression in spontaneous EAE should provide insight regarding the potential application of laquinimod to MS treatment. Results of this investigation demonstrate how the 2D2 × Th spontaneous EAE model can be used successfully for preclinical evaluation of a candidate MS treatment.

GLOSSARY

APC=
antigen-presenting cell;
BCL6=
B cell lymphoma 6;
DC=
dendritic cell;
EAE=
experimental autoimmune encephalomyelitis;
FDC=
follicular dendritic cell;
GC=
germinal center;
Ig=
immunoglobulin;
IL=
interleukin;
MHC=
major histocompatibility complex;
MOG=
myelin oligodendrocyte glycoprotein;
MS=
multiple sclerosis;
p=
peptide;
PD-1=
programmed cell death protein 1;
rMOG=
recombinant myelin oligodendrocyte glycoprotein;
Tfh=
T follicular helper

Footnotes

  • ↵* These authors contributed equally to this work.

  • Funding information and disclosures are provided at the end of the article. Go to Neurology.org/nn for full disclosure forms. The Article Processing Charge was paid by the authors.

  • Supplemental data at Neurology.org/nn

  • See editorial

  • Received June 6, 2016.
  • Accepted in final form June 30, 2016.
  • © 2016 American Academy of Neurology

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially.

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